PROJECT SUMMARY Opioids remain the gold standard for treating moderate to severe pain, but their use is limited by numerous adverse effects including tolerance, dependence, abuse, and overdose. Adverse effects could be avoided by combining an opioid with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Direct-acting serotonin type 2 (5-HT2) receptor agonists interact in a synergistic manner with the opioid morphine to produce antinociceptive effects, suggesting a 5-HT2 receptor agonist could be combined with small dose of an opioid to treat pain thereby lowering the risk associated with larger doses. However, little is known about interactions between 5-HT2 receptor agonists and other opioids, and it is unclear whether 5-HT2 receptor agonists enhance other adverse effects, particularly those relating to abuse or overdose or alter the consequences of repeated treatment with an opioid. Proposed studies evaluate the therapeutic potential of mixtures of opioids and 5-HT2 receptor agonists using highly translatable and well- established procedures to characterize the antinociceptive, respiratory-depressant (overdose), positive- reinforcing (abuse), and discriminative-stimulus (subjective) effects of drug mixtures as well as the impact of chronic treatment on the development of tolerance to and physical dependence on opioids. Studies in Aim 1 characterize acute interactions between opioids and 5-HT2 receptor agonists for antinociceptive effects and examine the contribution of 5-HT2 receptor subtypes. Studies in Aim 2 evaluate the acute respiratory- depressant, positive reinforcing, and discriminative stimulus effects of mixtures containing an opioid and a 5- HT2 receptor agonist. Studies in Aim 3 compare effects of daily dosing with a mixture of an opioid and a 5-HT2 receptor agonist to those of the opioid administered alone in order to evaluate changes in the development of tolerance and physical dependence. These studies will identify combinations of opioids and 5-HT2 receptor agonists that increase the therapeutic window of opioids by decreasing the dose of opioid necessary for therapeutic effects, while also reducing the adverse effects that currently limit the legitimate medical use of opioids (tolerance, dependence, abuse and overdose) and 5-HT2 receptor agonists (subjective effects). Using a species and procedures that are highly translatable to humans, these studies will provide proof-of-concept for this innovative approach to pain treatment and evaluate the utility of targeting 5-HT receptors for analgesic drug development.